The mechanisms underlying the profound modulation of parasite antigen-specific human T cell responses in lymphatic filariasis have been addressed by demonstrating the multiple pathways involved. By using live parasites and parasite antigen, we have demonstrated that antigen presenting cell (APC) function is profoundly altered in filarial infection both at the transcriptional and protein level. Moreover, this APC dysfunction extends to TLR-3 and -4 signaling pathways. [unreadable] [unreadable] Beyond the APC dysfunction, T cells from patients with patent infection have induced pathways (SOCS genes, ubiquitin ligases, regulatory networks) that in concert prevent Th1-type T cell activation. Moreover, the induction of apoptosis appears to be a common mechanism by which live filarial parasites influence the host response (in dendritic cells and NK cells at least) and does so in a TRAIL- and caspase 3-dependent fashion. [unreadable] [unreadable] Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to study the spillover effect of the downregulation on responses and diseases that are non-parasitic. To this end, we have both clinical trials underway and in vitro models that have demonstrated the influence of pre-existing chronic helminth infection on susceptibility to mycobacteria, on modulating the response to aeroallergens, and potentially to HIV and malaria. Specifically, we have recently demonstrated that coincident filarial infections profoundly alter the pro-inflammatory and Th1/Th17 responses to malarial antigens (in filarial/malarial coinfections) and to mycobacterial antigens (in filarial/latent tuberculosis coinfections). The latter appears to involve both PD-1 and CTLA-4. [unreadable] [unreadable] Because much of the pathology associated with filarial infections is related to lymphatic dysfunction, we have established a human in vitro model to examine parasite/lymphatic cell interaction. By purifying lymphatic endothelial cells (LEC) from blood vascular endothelial cells (BEC), we have been able to demonstrate the presence of filarial parasite molecules that induce lymphangiogenesis and abnormal vasculuar tube formation. In addition, the global changes in gene expression induced by filarial parasites in LEC have been characterized.[unreadable] [unreadable] Filarial-induced CD4+ and CD8+ responses have been characterized fully (using microarray/quantitative RT-PCR) in both the generally more-responsive expatriate patients and the less responsive indigenous (with lifelong exposure) filarial-infected patients. These data provide clues to the pathways induced by infection and those systemic alterations seen in chronic helminth infection. Using a very similar approach, we have also been able to demonstrate expression signatures among patients infected with closely-related by phylogenetically distinct parasites (e.g., Loa loa and Mansonella perstans).